Tag Archives: temporal lobe epilepsy

In vitro modulation of seizure-like activity with beta-cyclodextrin-complexed rufinamide

Rita-Judit Kiss1, Zsolt András Nagy2, Ádám Szentes2, Ágnes Csüdör2, Andrea Máthé2, Henrietta Makó2, Előd Bomher2, Ádám József Berki3, Zsolt Gáll4, Tibor Szilágyi1, Károly Orbán-Kis1

1. Physiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
2. George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
3. Department of Neurology, Semmelweis University, Budapest, Hungary
4. Pharmacology and Clinical Pharmacy Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2024-0020

Objective: The global health concern of pharmacoresistant epilepsy necessitates innovative therapeutic strategies. Drug resistance often arises due to complex pharmacokinetic challenges. Beta-cyclodextrin, known for enhancing drug solubility and stability, offers a potential solution for improving the efficacy of antiseizure medications. This study aims to investigate the impact of beta-cyclodextrin-complexed rufinamide on seizure-like activity using an in vitro model of temporal lobe epilepsy.
Methods: Seizure-like neuronal activity was induced using a low-magnesium model. Local field potentials were recorded from transverse rat hippocampal slices. Rufinamide was solubilized using beta-cyclodextrin and administered at 100 micromolar concentration. The impact on various seizure-like parameters and time-resolved phase-amplitude coupling was assessed.
Results: Rufinamide increased the duration of the preictal phase while reducing the duration of ictal and postictal phases. The frequency of seizure-like events was higher in rufinamide. No significant change was observed in the firing rate of the first 10 ictal spikes, but the firing frequency of the second set of 10 ictal spikes was higher during rufinamide perfusion. Time-resolved phase-amplitude coupling maximum analysis did not reveal significant differences between the control and rufinamide treatment.
Conclusions: Beta-cyclodextrin-solubilized rufinamide significantly modulates seizure-like event dynamics, exhibiting both anticonvulsant and proconvulsant effects. While the compound shortened seizure-like activity, it increased the frequency of seizure-like events. Our observations suggest a need for further investigation into the solubilization method and its impact on rufinamide’s bioavailability. Dose-dependent effects and underlying molecular mechanisms should also be explored to enhance the pharmacological properties of antiseizure medications.

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Effect of carbamazepine-beta-cyclodextrin inclusion complex on seizure-like events in an in vitro model of temporal lobe epilepsy

Rita-Judit Kiss1, Ágnes Csüdör2, Máté Sárosi2, Zsolt András Nagy2, Ádám Szentes2, Zsolt Gáll3, Tibor Szilágyi1, Károly Orbán-Kis1

1. Physiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
2. George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
3. Pharmacology and Clinical Pharmacy Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2024-0007

Objective: Pharmacoresistant epilepsy represents a significant global health challenge, necessitating novel therapeutic approaches. Despite advances in antiseizure medications, many patients remain treatment-resistant partially due to complex pharmacokinetic issues. Beta-cyclodextrin, known for enhancing drug solubility and stability, offers potential solutions by forming inclusion complexes, thereby improving anti-seizure medication’s efficacy. This study aimed to investigate the effect of beta-cyclodextrin and beta-cyclodextrin-complexed carbamazepine on epileptiform activities, using an in vitro model of temporal lobe epilepsy.
Methods: Seizure-like neuronal activity was induced using the low-magnesium model. Local field potentials were recorded from transverse rat hippocampal slices immersed in epileptogenic artificial cerebrospinal fluid, followed by the administration of either beta-cyclodextrin or carbamazepine, the latter in 100 micromolar concentration.
Results: Beta cyclodextrin, applied alone, significantly reduced the duration of interictal and ictal phases while increasing the frequency of seizure-like events. Carbamazepine exhibited an important anticonvulsant effect, significantly reducing ictal and postictal phase durations. However, the frequency of seizure-like events was increased. Notably, in some of the slices, carbamazepine completely suppressed epileptiform activity.
Conclusions: Beta cyclodextrin had an effect on its own; it shortened seizure durations and increased their frequency. Carbamazepine in complexed form, as used in our study, exhibited anticonvulsant efficacy, emphasizing the feasibility of solubility enhancement by this method. This study provides insights into potential therapeutic strategies for pharmacoresistant temporal lobe epilepsy, improving the pharmacological properties of the drugs. As cyclodextrins emerge as promising excipients for antiepileptic drugs with poor solubility, more effort is needed in order to elucidate the underlying mechanisms of their effects.

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The effect of amygdala low-frequency stimulation on inter-hippocampal connectivity in the pilocarpine model of epilepsy

István Mihály, Ádám-József Berki, Károly Orbán-Kis, Zsolt Gáll, Réka-Barbara Bod, Tibor Szilágyi

George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2021-0004

Objective: The aim of our study was to investigate the effect of amygdala low-frequency stimulation on inter-hippocampal network synchronization by using the phase locking value (PLV) in order to establish new biomarkers of treatment efficacy in a temporal lobe epilepsy model.
Materials and Methods: The lithium-pilocarpine model of epilepsy was used to induce status epilepticus in male Wistar rats. Afterward, seizures were scored based on continuous video recordings. 8 weeks after status epilepticus electrodes were implanted: a stimulating electrode in the left basolateral amygdala and bilaterally two hippocampal recording electrodes in both pilocarpine-treated and age-matched control rats (N=7). 10 Pilo and 4 control animals were stimulated daily for 10 days with 4 packages of 50 seconds 4Hz trains. Inter-hippocampal PLVs were measured offline before and after stimulation trains in delta (1-4Hz), theta (4-12Hz), gamma (30-100Hz), HFO (100-150Hz), ripple (150-250Hz), and fast ripple (250-600Hz) bands using Brainstorm software.
Results: The PLV before the stimulation was significantly lower in epileptic animals compared to controls in the delta, theta, and gamma bands. The PVLs of epileptic animals were increased by low-frequency stimulation in delta and theta bands. The PLVs in HFO and ripple band correlated positively with the changes in seizure rate, while the PLVs in the delta, theta, and gamma correlated positively with the changes in seizure duration.
Conclusion: Amygdala low-frequency stimulation improved the impaired synchrony between the two hippocampi in low-frequency bands. The phase locking value could be useful to evaluate the efficiency of therapeutic interventions in temporal lobe epilepsy.

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Cortical Epileptogenesis of Slowly Kindled Freely Moving Rats

Orbán-Kis K*, Száva Iringó, Szilágyi T

Department of Physiology, University of Medicine and Pharmacy Tirgu Mures, Romania

DOI: 10.1515/amma-2015-0003

Objective. Epilepsy is a neurological disorder that can be caused by many underlying pathologies. The epileptic and interictal manifestations that appear during the progression of chronic epilepsy are still not understood completely. One of the most frequent forms of this disease is temporal lobe epilepsy in which is clear involvement of the hippocampal formation. In order to study the electrografic progression of untreated seizures we used amygdala kindling in freely moving rats.
Methods. Seven animals were implanted with bilateral hippocampal and prefrontal electrodes. A bipolar electrode, implanted in the lateral nuclei of the left amygdala was used for stimulation. The kindled group of animals was stimulated daily with the minimum current intensity needed to reach the afterdischarge threshold. Behavioral changes during kindling were scored according to the Racine scale.
Results. The average seizure severity on the Racine scale was 2.6±0.4 by day 6 and 4.4±0.6 by day 20. The first spontaneous seizures appeared after 31 days of stimulation. During spontaneous seizures the preictal spike full width at half maximum increased gradually from 51±4msec to 110±5msec (p < 0.05) whereas the amplitude of the negative field potential deflection increased by 62% (p < 0.05).
|Conclusions. Our study showed that the progression of temporal lobe epilepsy, as seen in humans, can be reproduced in the kindling model with high fidelity. This study confirms in vivo the increase in preictal spike duration as well as the increase of the amplitude of negative field potential deflection during the preictal period.

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